tbuckley/cabot-search huggingface dataset:
Global burden of type 2 diabetes in adolescents and young adults, 1990-2019: systematic analysis of the Global Burden of Disease Study 2019
Authors: Jinchi Xie, Maoqing Wang, Zhiping Long, Hua Ning, Jingkuo Li, Yukun Cao, Yunfei Liao, Gang Liu, Fan Wang, An Pan
Journal: BMJ (2022)

Abstract Objective To estimate the global burden of type 2 diabetes in adolescents and young adults (aged 15-39 years) from 1990 to 2019. Design Systematic analysis. Data source Global Burden of Disease Study 2019. Participants aged 15-39 years from 204 countries and territories, 1990-2019. Main outcomes measures Age standardised incidence rate, age standardised disability adjusted life years (DALY) rate, and age standardised mortality rate for type 2 diabetes in people aged 15-39 years from 1990 to 2019, and proportional DALY attributable to different risk factors. Results From 1990 to 2019, significant increases in age standardised incidence rate and age standardised DALY rate were found for type 2 diabetes in adolescents and young adults globally (P&lt;0.001). Age standardised incidence rate (per 100 000 population) increased from 117.22 (95% confidence interval 117.07 to 117.36) in 1990 to 183.36 (183.21 to 183.51) in 2019, and age standardised DALY rate (per 100 000 population) increased from 106.34 (106.20 to 106.48) in 1990 to 149.61 (149.47 to 149.75) in 2019. The age standardised mortality rate (per 100 000 population) was modestly increased from 0.74 (0.72 to 0.75) in 1990 to 0.77 (0.76 to 0.78) in 2019. When grouped by countries with different sociodemographic indexes, countries with a low-middle and middle sociodemographic index had the highest age standardised incidence rate and age standardised DALY rate in 2019, whereas countries with a low sociodemographic index had the lowest age standardised incidence rate but the highest age standardised mortality rate. Women generally had higher mortality and DALY rates than men at ages &lt;30 years, but differences between the sexes were reversed in those aged &gt;30 years except in countries with a low sociodemographic index. The main attributable risk factor for DALY for early onset type 2 diabetes was high body mass index in all regions by sociodemographic index. The proportional contribution of other risk factors varied across regions, however, with higher proportions of ambient particulate air pollution and smoking in countries with a high sociodemographic index and higher proportions of household air pollution from solid fuels and diet low in fruit in countries with a low sociodemographic index. Conclusions Early onset type 2 diabetes is a growing global health problem in adolescents and young adults, especially in countries with a low-middle and middle sociodemographic index. A greater disease burden in women aged &lt;30 years was found. Specific measures are needed in countries with different levels of socioeconomic development because of the variable attributable risk factors for type 2 diabetes in adolescents and young adults.
Prostate Cancer Screening with PSA and MRI Followed by Targeted Biopsy Only
Authors: Jonas Hugosson, Marianne Månsson, Jonas Wallström, Ulrika Axcrona, Sigrid V. Carlsson, Lars Egevad, Kjell Geterud, Ali Khatami, Kimia Kohestani, Carl-Gustaf Pihl, Andreas Socratous, Johan Stranne, Rebecka Arnsrud Godtman, Mikael Hellström
Journal: New England Journal of Medicine (2022)

Screening for prostate cancer is burdened by a high rate of overdiagnosis. The most appropriate algorithm for population-based screening is unknown.
Healthspan and chronic disease burden among young adult and middle-aged male former American-style professional football players
Authors: Rachel Grashow, Taylor Valencia Shaffer-Pancyzk, Inana Dairi, Hang Lee, Dean Marengi, Jillian Baker, Marc G Weisskopf, Frank E Speizer, Alicia J Whittington, Herman A Taylor, Dylan Keating, Adam Tenforde, James Sawalla Guseh, Meagan M Wasfy, Ross Zafonte, Aaron Baggish
Journal: British Journal of Sports Medicine (2022)

To examine the relationships between age, healthspan and chronic illness among former professional American-style football (ASF) players.
Risk of total hip arthroplasty after elite sport: linking 3304 former world-class athletes with the Norwegian Arthroplasty Register
Authors: Daniel Hoseth Nilsen, Ove Furnes, Gard Kroken, Trude Eid Robsahm, Marianne Bakke Johnsen, Lars Engebretsen, Lars Nordsletten, Roald Bahr, Stein Atle Lie
Journal: British Journal of Sports Medicine (2022)

Objectives At present, there is no cure for osteoarthritis (OA), but severe hip joint degeneration can require total hip arthroplasty (THA). The literature on OA after elite sport is limited. We hypothesise that elite athletic activity increases the risk of receiving a THA later in life. Methods We linked a cohort of former Norwegian world-class athletes (1402 females and 1902 males, active 1936–2006) to the Norwegian Arthroplasty Register (THA performed 1987–2020). We used standardised incidence ratio (SIR), one-minus Kaplan-Meier and relative Cox regression (relative HR, RHR), with 95% CIs, and funnel plots at age 75, to assess THA risk for different sport disciplines, joint impact categories of sport disciplines and sex. The risk of THA for the corresponding general Norwegian population was used as reference. Results We found an overall increased risk for THA for the former elite athletes (SIR 2.11, 95% CI 1.82 to 2.40) at age 75 years, compared with the general population. THA risk at age 75 years was 11.6% for female athletes and 8.3% for male athletes. SIR was 1.90 (95% CI 1.49 to 2.31) for female and 2.28 (95% CI 1.87 to 2.70) for male athletes. Among males, high joint impact sport disciplines were associated with increased risk compared with low-impact sport disciplines (RHR 1.81, 95% CI 1.06 to 3.08, p=0.029). Conclusion Having been an elite athlete was associated with a doubling of THA risk compared with the general population for both sexes. High joint impact sport disciplines were associated with subsequent THA for male athletes.
Suggestions for improving healthcare for transgender and gender diverse people in the United States
Authors: Jae Puckett, Rowan Giffel, Felix Brown, Connor Gallik, Devon Kimball, Henry Chu, Brian S. Mustanski, Michael E. Newcomb
Journal: International Journal of Transgender Health (2022)

Introduction: Transgender and gender diverse (TGD) individuals face disproportionate barriers to accessing affirming healthcare, ranging from individual practitioners' biases to financial constraints and societal-level cisnormativity.Method: This study identified suggestions for improving healthcare from 420 TGD individuals in the United States. Participants responded to an open-ended question about their suggestions for improving healthcare for TGD people. These responses were then coded using thematic analysis, resulting in 22 specific codes under 6 themes.Results: Results indicated a need for eliminating cisnormativity, taking a holistic approach with clients, adjusting conceptual frameworks for care, eliminating accessibility barriers, promoting affirmative interactions with TGD clients, and providing TGD-affirmative training for providers. Notably, these suggestions spanned from the broader, cultural level regarding general understandings of TGD people and gender to micro-level interactions.Conclusions: This study provides important tools for improving TGD care via a reduction of barriers and an increase in competency and affirmation.
Th2 high and mast cell gene signatures are associated with corticosteroid sensitivity in COPD
Authors: Alen Faiz, Stelios Pavlidis, Chih-Hsi Kuo, Anthony Rowe, Pieter S Hiemstra, Wim Timens, Marijn Berg, Marissa Wisman, Yi-Ke Guo, Ratko Djukanović, Peter Sterk, Kerstin B Meyer, Martijn C Nawijn, Ian Adcock, Kian Fan Chung, Maarten van den Berge
Journal: Thorax (2022)

Rationale Severe asthma and chronic obstructive pulmonary disease (COPD) share common pathophysiological traits such as relative corticosteroid insensitivity. We recently published three transcriptome-associated clusters (TACs) using hierarchical analysis of the sputum transcriptome in asthmatics from the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) cohort comprising one Th2-high inflammatory signature (TAC1) and two Th2-low signatures (TAC2 and TAC3). Objective We examined whether gene expression signatures obtained in asthma can be used to identify the subgroup of patients with COPD with steroid sensitivity. Methods Using gene set variation analysis, we examined the distribution and enrichment scores (ES) of the 3 TACs in the transcriptome of bronchial biopsies from 46 patients who participated in the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease COPD study that received 30 months of treatment with inhaled corticosteroids (ICS) with and without an added long-acting β-agonist (LABA). The identified signatures were then associated with longitudinal clinical variables after treatment. Differential gene expression and cellular convolution were used to define key regulated genes and cell types. Measurements and main results Bronchial biopsies in patients with COPD at baseline showed a wide range of expression of the 3 TAC signatures. After ICS±LABA treatment, the ES of TAC1 was significantly reduced at 30 months, but those of TAC2 and TAC3 were unaffected. A corticosteroid-sensitive TAC1 signature was developed from the TAC1 ICS-responsive genes. This signature consisted of mast cell-specific genes identified by single-cell RNA-sequencing and positively correlated with bronchial biopsy mast cell numbers following ICS±LABA. Baseline levels of gene transcription correlated with the change in RV/TLC %predicted following 30-month ICS±LABA. Conclusion Sputum-derived transcriptomic signatures from an asthma cohort can be recapitulated in bronchial biopsies of patients with COPD and identified a signature of airway mast cells as a predictor of corticosteroid responsiveness.
Prevalence and Penetrance of Rare Pathogenic Variants in Neurodevelopmental Psychiatric Genes in a Health Care System Population
Authors: Hermela Shimelis, Matthew T. Oetjens, Lauren K. Walsh, Karen E. Wain, Masa Znidarsic, Scott M. Myers, Brenda M. Finucane, David H. Ledbetter, Christa Lese Martin
Journal: American Journal of Psychiatry (2022)

Autism, schizophrenia, and other clinically distinct neurodevelopmental psychiatric disorders (NPDs) have shared genetic etiologies, including single-gene and multigenic copy number variants (CNVs). Because rare variants are primarily investigated in clinical cohorts, population-based estimates of their prevalence and penetrance are lacking. The authors determined the prevalence, penetrance, and NPD risk of pathogenic single-gene variants in a large health care system population.
Diagnosis of immediate reactions to amoxicillin: Comparison of basophil activation markers <scp>CD63</scp> and <scp>CD203c</scp> in a prospective study
Authors: Jose A. Céspedes, Rubén Fernández‐Santamaría, Adriana Ariza, Gador Bogas, Inmaculada Doña, Carmen Rondón, María Salas, Marina Labella, Cecilia Frecha, Cristobalina Mayorga, María J. Torres, Tahia D. Fernández
Journal: Allergy (2022)

Amoxicillin (AX) combined or not with clavulanic acid (CLV) is frequently involved in IgE-mediated reactions. Drug provocation test (DPT) is considered as the gold standard for diagnosis, although contraindicated in high-risk patients. Basophil activation test (BAT) can help diagnose immediate reactions to beta-lactams, although controversy exists regarding the best activation marker. We have performed a real-life study in a prospective cohort to analyze the real value of BAT as diagnostic tool and the best activation marker, CD63 and CD203c, for the evaluation of immediate reactions to these drugs.We prospectively evaluated patients with a clinical suspicion of immediate reactions after AX or AX-CLV administration during a 6-year period. The allergological work-up was done following the EAACI recommendations. BAT was performed in all patients using CD63 and CD203c as activation markers.In AX-allergic patients, both activation markers, CD63 and CD203c, showed similar SE values (48.6% and 46.7%, respectively); however, specificity was of 81.1% and 94.6%, respectively, with CD203c showing good positive predictive value and like-hood ratio. In CLV-allergic patients, CD203c showed higher SE (50%) than CD63 (42.9%), maintaining the same value of SP (80%). Combining the results of both markers can slightly increase the sensitivity (51.4% for AX and 54.8% for CLV), although decreasing the specificity (79.7% and 73%, respectively). Interestingly, all patients with an anaphylactic shock showed a positive BAT to CLV using CD203c.BAT using CD203c showed a good confirmatory power, especially for AX allergy. Placing BAT as a first step in the diagnostic procedure can help reduce the need of performing a complete allergological work-up in 46.6% of patients, diminishing the risk of reinducing allergic reactions.
Exploring the Potential of PEG‐Heparin Hydrogels to Support Long‐Term Ex Vivo Culture of Patient‐Derived Breast Explant Tissues
Authors: Maria K. Koch, Akhilandeshwari Ravichandran, Berline Murekatete, Julien Clegg, Mary Teresa Joseph, Madison Hampson, Mitchell Jenkinson, Hannah S. Bauer, Cameron Snell, Cheng Liu, Madeline Gough, Erik W. Thompson, Carsten Werner, Dietmar W. Hutmacher, Larisa M. Haupt, Laura J. Bray
Journal: Advanced Healthcare Materials (2022)

Breast cancer is a complex, highly heterogenous, and dynamic disease and the leading cause of cancer-related death in women worldwide. Evaluation of the heterogeneity of breast cancer and its various subtypes is crucial to identify novel treatment strategies that can overcome the limitations of currently available options. Explant cultures of human mammary tissue have been known to provide important insights for the study of breast cancer structure and phenotype as they include the context of the surrounding microenvironment, allowing for the comprehensive exploration of patient heterogeneity. However, the major limitation of currently available techniques remains the short-term viability of the tissue owing to loss of structural integrity. Here, an ex vivo culture model using star-shaped poly(ethylene glycol) and maleimide-functionalized heparin (PEG-HM) hydrogels to provide structural support to the explant cultures is presented. The mechanical support allows the culture of the human mammary tissue for up to 3 weeks and prevent disintegration of the cellular structures including the epithelium and surrounding stromal tissue. Further, maintenance of epithelial phenotype and hormonal receptors is observed for up to 2 weeks of culture which makes them relevant for testing therapeutic interventions. Through this study, the importance of donor-to-donor variability and intra-patient tissue heterogeneity is reiterated.
Direct intramyocardial injection of VEGF mRNA in patients undergoing coronary artery bypass grafting
Authors: Vesa Anttila, Antti Saraste, Juhani Knuuti, Marja Hedman, Pekka Jaakkola, Karl-Ludwig Laugwitz, Markus Krane, Anders Jeppsson, Saara Sillanmäki, Jaya Rosenmeier, Pernilla Zingmark, Anna Rudvik, Pavlo Garkaviy, Christina Watson, Menelas N. Pangalos, Kenneth R. Chien, Regina Fritsche-Danielson, Anna Collén, Li-Ming Gan
Journal: Molecular Therapy (2022)

Vascular endothelial growth factor A (VEGF-A) has therapeutic cardiovascular effects, but delivery challenges have impeded clinical development. We report the first clinical study of naked mRNA encoding VEGF-A (AZD8601) injected into the human heart. EPICCURE (ClinicalTrials.gov: NCT03370887) was a randomized, double-blind study of AZD8601 in patients with left ventricular ejection fraction (LVEF) 30%-50% who were undergoing elective coronary artery bypass surgery. Thirty epicardial injections of AZD8601 (total 3 mg) or placebo in citrate-buffered saline were targeted to ischemic but viable myocardial regions mapped using quantitative [
Correction: How T-lymphoblastic leukemia can be classified based on genetics using standard diagnostic techniques enhanced by whole genome sequencing
Authors: Janine Müller, Wencke Walter, Claudia Haferlach, Heiko Müller, Irene Fuhrmann, Martha-Lena Müller, Henning Ruge, Manja Meggendorfer, Wolfgang Kern, Torsten Haferlach, Anna Stengel
Journal: Leukemia (2022)
First hemophilia B gene therapy approved: More than two decades in the making
Authors: Roland W. Herzog, Thierry VandenDriessche, Margareth C. Ozelo
Journal: Molecular Therapy (2022)

Prevention of bleeds in patients with the severe form of the X-linked bleeding disorder hemophilia B requires frequent intravenous injections of coagulation factor IX (FIX) protein. Gene therapy has the potential to accomplish sustained correction of the bleeding tendency following a single drug administration. In the late 1990s, a body of preclinical work rapidly evolved, demonstrating the ability of adeno-associated viral (AAV) gene transfer to skeletal muscle or liver to generate lasting therapeutic levels of FIX in small and large animal models of the disease. Now, roughly 25 years after the initial demonstration that gene therapy could potentially cure hemophilia B in animals, the first gene therapy drug for hemophilia B has obtained regulatory approval in the United States: Hemgenix (etranacogene dezaparvovec). Hemgenix is an AAV5 vector expressing the hyper-active FIX-Padua variant for hepatic gene transfer in adult patients. This CSL Behring gene therapy product (initially developed by UniQure) was approved by the Food and Drug Administration (FDA) based on safety and effectiveness in studies of adult men with severe or moderately severe disease. It is currently the most expensive drug in the world with a price tag of $3.5 million. In clinical trials, FIX activity increased to nearly the normal range 2 years after vector infusion, consistent with decreased incidence of bleeding (annualized bleeding rates, ABR), and approximately 95% of treated patients remained off prophylaxis (i.e., did not require FIX protein infusions to prevent bleeds). The availability of the first FDA-approved gene therapy product for hemophilia B offers a new treatment option for patients afflicted by this bleeding disorder. This is also the first FDA-approved liver-directed gene therapy product, thus having broad implications for the field at large.
Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study
Authors: Mark N. Brook, Holly Ní Raghallaigh, Koveela Govindasami, Tokhir Dadaev, Reshma Rageevakumar, Diana Keating, Nafisa Hussain, Andrea Osborne, Artitaya Lophatananon, Kenneth R. Muir, Zsofia Kote-Jarai, Rosalind A. Eeles
Journal: European Urology (2022)

A family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis. To determine how the number, degree, and age of a PrCa patient’s affected relatives are associated with OS and PCSS of those already diagnosed with PrCa. The UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16 340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). The primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by calculating hazard ratios from Cox proportional hazard regression models, adjusting for relevant factors. A stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all-cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75–0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases. Based on the investigation of the type and timing of relatives’ cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of the disease. This study provides information for clinicians guiding patients and their relatives based on their familial risk. It shows the importance of screening and awareness programmes, which are likely to improve survival among men with an FH. We were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16 340 patients, categorised them according to the strength of their family history, and found that the stronger their family history, the better they did in terms of overall survival. We looked at the type and timing of patients’ diagnoses compared with those of their relatives and found that this effect is likely to be explained by awareness, which indicates the importance of screening and awareness programmes.
Microenvironmental ammonia enhances T cell exhaustion in colorectal cancer
Authors: Hannah N. Bell, Amanda K. Huber, Rashi Singhal, Navyateja Korimerla, Ryan J. Rebernick, Roshan Kumar, Marwa O. El-derany, Peter Sajjakulnukit, Nupur K. Das, Samuel A. Kerk, Sumeet Solanki, Jadyn G. James, Donghwan Kim, Li Zhang, Brandon Chen, Rohit Mehra, Timothy L. Frankel, Balázs Győrffy, Eric R. Fearon, Marina Pasca di Magliano, Frank J. Gonzalez, Ruma Banerjee, Daniel R. Wahl, Costas A. Lyssiotis, Michael Green, Yatrik M. Shah
Journal: Cell Metabolism (2022)